Phenobarbital suppresses vitamin D3 25-hydroxylase expression: a potential new mechanism for drug-induced osteomalacia

Biochem Biophys Res Commun. 2007 Jun 8;357(3):603-7. doi: 10.1016/j.bbrc.2007.03.177. Epub 2007 Apr 9.

Abstract

Prolonged therapy with phenobarbital may cause vitamin D deficiency or osteomalacia. In the current study, we propose a novel mechanism for drug-induced osteomalacia involving impaired bioactivation of vitamin D(3) due to decreased 25-hydroxylation of vitamin D(3) in liver. The present data, using the pig as model, demonstrate direct effects by phenobarbital on the expression of CYP27A1 and CYP2D25, two important 25-hydroxylases. Treatment by phenobarbital markedly reduced the rate of 25-hydroxylation by primary hepatocytes and suppressed the cellular CYP27A1 mRNA levels. The rate of 25-hydroxylation by two different purified 25-hydroxylases, microsomal CYP2D25, and mitochondrial CYP27A1, respectively, was dose-dependently inhibited by phenobarbital. Reporter assay experiments in liver-derived HepG2 cells revealed a marked PXR-mediated transcriptional downregulation of the CYP2D25 promoter. In addition, the data indicate that phenobarbital might affect the mRNA stability of CYP2D25. Taken together, the data suggest that vitamin D(3) 25-hydroxylation may be suppressed by phenobarbital. A downregulation of 25-hydroxylation by phenobarbital may explain, at least in part, the increased risk of osteomalacia, bone loss, and fractures in long-term phenobarbital therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / adverse effects
  • Anticonvulsants / pharmacology
  • Cell Line, Tumor
  • Cells, Cultured
  • Cholestanetriol 26-Monooxygenase / antagonists & inhibitors*
  • Cholestanetriol 26-Monooxygenase / genetics
  • Cholestanetriol 26-Monooxygenase / metabolism
  • Constitutive Androstane Receptor
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Hydroxylation / drug effects
  • Luciferases / genetics
  • Luciferases / metabolism
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Osteomalacia / chemically induced
  • Osteomalacia / enzymology
  • Osteomalacia / metabolism
  • Phenobarbital / adverse effects
  • Phenobarbital / pharmacology*
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Retinoid X Receptors / genetics
  • Retinoid X Receptors / metabolism
  • Swine
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection
  • Vitamin D / metabolism

Substances

  • Anticonvulsants
  • Constitutive Androstane Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Fusion Proteins
  • Retinoid X Receptors
  • Transcription Factors
  • Vitamin D
  • Luciferases
  • Cholestanetriol 26-Monooxygenase
  • Phenobarbital